Obesity is a major risk factor for type II diabetes and metabolic syndromes. Increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. Hypothalamic neurons, including anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic Agouti-related peptide (AgRP) neurons, integrate multiple metabolic cues (e.g. leptin and insulin) to provide a coordinated control of energy and glucose homeostasis. We found that an adaptor protein, growth factor receptor-bound protein 10 (Grb10), is abundantly expressed in the hypothalamus, and its expression is elevated by HFD feeding. Further, Grb10 inhibits both leptin and insulin actions in neurons. Importantly, deletion of Grb10 in hypothalamic neurons leads to profound lean phenotypes in mice. Based on these, we hypothesized that Grb10 promotes body weight gain by negative regulation of leptin and insulin signaling in hypothalamic neurons. The first objective will focus on anorexigenic POMC neurons. We will generate two opposite genetic mouse models: one with Grb10 deleted in mature POMC neurons and the other with Grb10 overexpressed in mature POMC neurons. We will use these loss- and gain-of-function models to determine how Grb10 in POMC neurons regulates energy and glucose balance, modulates leptin and/or insulin signaling pathways, and controls firing activities and gene expression. The second objective will focus on orexigenic AgRP neurons. We will use the similar approaches to delete or overexpress Grb10 in mature AgRP neurons. We will use these loss- and gain-of-function models to determine the physiological role of Grb10 in AgRP neurons in the regulation of energy/glucose balance. Further, we will explore the cellular and molecular mechanisms by which Grb10 modulates leptin/insulin-induced signaling pathways and regulates firing activity and gene transcription of AgRP neurons. The third objective is to use in vitro approaches to determine the molecular mechanisms for Grb10 to inhibit leptin signaling. To this end, we will first map the interacting regions between Grb10 and the leptin receptor molecules, and then determine if such interaction provides a mechanism for Grb10 to inhibit leptin signaling. These studies could lead to important advances in our understandings regarding the central regulation of energy/glucose homeostasis. We may also provide mechanistic insights on the fundamental biology for leptin/insulin signaling in the brain. Finally, the proposed studies may carry translational impact on human health, as we may identify brain Grb10 as a rational target for potential anti-obesity therapy.